Streptomycin-polymyxin-bacitracin composition



Patented Apr. 29, 1952 STREPTOMYCIN-POLYIWYXIN-BACITRACIN COMPOSITION Henry Welch, Silver Spring, Md., assignor to the United States of America No Drawings Application October 11, 1949,

' Serial No. 120,811

..(Granted under the act of March 3, 1883, as

3 Claims.

amended April 30, 1928; 370 0. G. 757) The present invention relates to a pharmaceutical composition and more especially to a composition which is particularly adapted to pre-operative and post-operative treatment of patients prior to and following abdominal surgery, since it markedly reduces the number of bacteria in the intestinal tract. Because of its bactericidal and bacteriostatic activity, this pharmaceutical composition is also adapted to the treatment of a wide variety of infections of the intestinal tract.

Various antibacterial preparations have been employed in abdominal surgery and for the treatment of infections of the intestinal tract. Streptomycin has been used, but it is ineffective against anerobic organisms and many Gram- '-negative organisms develop resistance to this drug rapidly and although initially the intestinal bacterial content is reduced, within a matter of two to three days the bacterial flora has been replaced by organisms resistant to the drug. This is especially true of the coliform type of bacteria. (Ref. Herfort, R. A., and Standard, Samuel: Annals of Surgery, 2854;128:1948.)

Penicillin has been used in an attempt to destroy bacteria in the intestinal tract but it is effective only against Gram-positive organisms, and as a matter of fact is inactivated by enzymes produced by Gram-negative organisms. Hence it has not been found to be very successful in have been used extensively as intestinal antibacterial agents also, but their action is highly (Ref. Ravdin, I. 8., Zintel, H. A., and

selective. Bender, D. 1-1.: Annals of Surgery, 1265:1947.)

The combination of streptomycin and glucuronolactone has been used to sterilize the intestinal tract with considerably more success than streptomycin alone, but this combination does not suppress the clostridia or bacteroides and, in addition, following treatment resistant strains of coliform organisms can be demonstrated in fecal specimens. (Ref. PulaskiyE. J Bulletin of U. S. Army Medicine, 9:49.)

In'accordance with this invention I have discovered that by combining streptomycin, polymyxin, and bacitracin there is obtained a composition which, according to clinical and bacteriological tests, approaches the ideal compound for reducing the bacterial fiora of the intestinal tract. This composition has an important advantage over others proposed in that it provides not only a rapid reduction in the intestinal bacteria, but is successful in maintaining a markedly reduced bacterial count in the intestinal tract over long periods of time.

The composition may be made in a liquid or dry form. In addition to the active ingredients of the composition, I may use various inert solids, particularly when the composition is made in the dry form.

The composition may be conveniently used in the form of tablets or capsules, or it may be suspended in liquid form in a menstruum of flavored gelatin. The tablets may be prepared by mixing theactive ingredients (streptomycin, polymyxin, and bacitracin) with excipients such as lactose, talc, cornstarch, binders, lubricants (calcium stearate) and, if necessary, flavoring oils such as methyl salicylate.

The tablet may be prepared by processes well known in the pharmaceutical industry such as by slugging or by a wet granulation process. The tablet made by the dry granulation process has the following composition:

Per tablet Streptomycin milligrams 250 Polymyxin do 20 Bacitracin units 5,000 Inert materials including excipients, binders, and lubricants, q. s. to gra-ms 0.5

' The capsules are prepared without excipients, lubricants and binders but by using the above formula with the active ingredients (streptomycin, polymyxin, bacitracin) enclosed in a hard gelatin capsule of proper size.

The composition can be prepared by dissolving in water 3 grams of streptomycin, 240 milligrams of polymyxin, and 60,000 units of bacitracin with one box of commercially available cherry Jello. The latter preparation was the first One utilized in clinical studies and the cherry Jello was chosen because of its ability to neutralize the taste of the antibiotics, two of which (bacitracin and polymyxin) are extremely unpalatable.

' The proportions of the various ingredients in my composition may be varied widely provided the patient 'is given the proper dosage of the equal portions and to take one portion twice 7 daily. The amount of antibiotics in the tablets and capsules is governed primarily by the size of the tablet or capsule.

In the composition where reference is made to streptomycin is meant each of the several antibiotic substances produced by the growth of Streptomyces griseus including dihydrostreptomycin. Where reference is made to polymyxin is meant each of the several antibiotic substances produced by the growth of Bacillus polymya'a. Similarly, where reference is made to bacitracin is meant each of the several antibiotic substances produced by the growth of Bacillus subtilis var. Tracy.

The effect of this streptomycin, polymyxin, bacitracin composition on the intestinal bacterial flora of man was determined, using six normal adult males. At the same time another pharmaceutical preparation called glucomycin was tested for comparison in the same number of subjects. Glucomycin is a mixture of streptomycin and glucuronolactone, and is said to overcome the deficiencies of streptomycin in that the coliform portion of the intestinal flora does not return to its former number under treatment even though when treatment is discontinued and the coliform count returns to normal the organisms are found to be highly resistant to streptomycin. As a further control and to show the additive effect of the composition over polymyxin alone, another group of six volunteers was treated with polymyxin. Neither bacitracin nor streptomycin was tested in this study since the former, when used alone, has been shown to cause the development of resistant strains of bacteria in the intestinal tract and the latter (bacitracin) is active against only the Gram-positive type of organisms.

The daily dose of glucomycin was twenty one-half grain tablets, a total of two grams of streptomycin and eight grams of glucuronolactone. The daily dose of polymyxin was one (1) one hundred milligram tablet while the daily dose of streptomycin-bacitracin-polymyxin composition was four tablets, a total of one gram of streptomycin, twenty thousand units of bacitracin and eighty milligrams of polymyxin.

The efiect on the intestinal bacterial flora in each volunteer was determined by first obtaining the control bacterial counts followed by administering the appropriate material for a period of ten days and studying the bacterial flora in daily fecal specimens. The treatment schedule was then discontinued for eight days to allow the intestinal bacterial flora to return to normal, then the treatment schedule was started again and continued for six days to determine whether the first regimen had resulted in resistant bacterial types which would fail to respond to a second course of the same therapeutic agent. In numerous investigations of this type reported in the literature, the coliform organisms have been used as an index or" the effect of antibacterial agents on the intestinal flora of man. These organisms are usually involved directly in infeotions following abdominal surgery and not infrequently are associated with gastro-intestinal pathology. (Ref. Bulletin, Johns Hopkins Hospi- 4 tal 71:213-234 (1942).) Consequently, the coliform organisms were chosen to study the comparative effectiveness of the three preparations. The results are illustrated in the table.

Tabla-Bacterial counts showing the comparative effect of glucomycin, polymyxin and streptomycin-polymyxin-bacitracin composition on coliform bacteria in the intestinal tract of 18 human male volunteers Numbers of Coliform Bacteria per Gm. of Wet Stool Date Treatment streptomycim Glucomycin Polymyxin gggg ggfi' Composition 8-10 Oontro)l (no 350, 000, 000 350, 000, 000 350, 000, 000

rug 8-20 Drug given 36, 000, 000 2, 430, 000 2, 170, 000 8-2l do 186, 000 4, 000, 000 1 200 d l 160 2,000, 000 1 160 9 1 23 567, 000 1 5O 2 8-30 N0 drug... 1 2 3, 700,000 0 8 3l do 0 3, 700, 000 0 l do 3, 600 16, 700. 000 0 9-2 to 9-6 do 49, 200, 000 53, 000, 000 50, 000, 000 9-7- Drug given. 24, 020, 000 37 000, 000 840, 000 do 2, 000, 000 20, 000,000 1 do 2,020,000 2,200,000 1 20 .do 1,700,000 0 do 0 1,700,000 0 do 40,000 0 9l3 to 9- N0 drug 5, 625 2, 150, 000 1, 750, 000

Fivo of the six patients treated showed absence of coliform bacteria.

Dose given:

Glucomycin: twenty 0.5 gm. tablets daily (2.0 gm. streptomycin, 8.0 gm. glucuronalactone) Streptomycin-polymyxin-bacitracin composition: four 0.5 gm. tablets (1.0 gm. streptomycin, mg. polymyxin, 40,000 units bacitracin) daily Polymyxin: one mg. tablet daily Inspection of the table shows that both the glucomycin and the streptomycin-bacitracinpolymyxin composition resulted during therapy in a reduction of the coliform organisms to zero. The streptomycin-bacitracin-polymyxin composition, however, resulted in a more rapid reduction of the coliform count. It should be noted that the streptomycin content of the composition was only one-half as much as that in the glucomycin. Thus the more than additive effect of the composition of the three drugs is apparent. This increased effectiveness of the composition is evident once again when the second dosage schedule was instituted (9-7). The count with the streptomycin-bacitracin-polymyxin composition fell from 50,000,000 to less than one million in one day, and was essentially zero by the second day. With glucomycin the drop was much slower, the count on the first day remaining 24,000,000 with 2,000,000 coliforms present on the a tendency to increase even during the administration of polymyxin.

v In addition to the effect of these three preparations on the coli orm bacteria, studies we made "'h the 18 male volunteers of th streptococci, the heat resistant organisms treated at 86 C. for 30 minutes) count of each stool specimen. In get reduction in numbers of organisi. pattern similar to that obtained 'iVl'fi form bacteria. it should be noted that a bacterial flora was eli iina-ted, yeasts the stools following he treatment with preparations total counts or" i were thereby increased.

inycin-polyrny markedly reduce the rumber or gastrointestinal tract, and especia negative collie-rm bacteria, it was treatment of ten of gastrc-in function. In nine these ten cad etiologic agent was not isolated. case diagnosed amoebic Amoebic dysentery is a i causative orgar Endamoeoc it relatively unaffected by three antibiotics Cl the composition. However, the 1 caused initially by the arno grave-ted seccn-c teria norm t Thus, from thi tandpoint polymy in composition re'eves symptoms of amoebic dysentery and aids in cure of the disease. Furthermore, since damoeba histoit'tica utilizes certain bacteria the intestinal tract for food, the reduction in the total number of bacteria reduces the food suppl necessary for the growth of the amoeba and helcs in their eradication. he chief con. plaint in all ten cases was per tent diarrhea, with secondary systems of a varied nature, such as abdominal pain, anorexia, an loss of weight. It is generally recognized that in the majority of cases presenting the above symptoms a specific etiologic agent is not usually identified. The opinion that in such cases bacteria which are normal inhabitants of the intestinal tract cause irritation of the gut resulting in the above men tioned symptoms. ,Bince the precise causative organism is not known in most of these cases the antibiotic composition herein described is designed to eliminate or supnress the greatest number or" he bacterial species normally present in the gastrointestinal tract. However, this antibiotic composition is also active against many known intestinal pathogens, such as the causative organisms of typhoid fever, paraty phoid fever, and bacillary dysentery.

The dosage used was the same in all cases. The drugs were administered either as a compressed tablet, in capsules, or the separate antibiotics were incorporated in a cherry flavored gelatin preparation. In any case, the total daily dose of the antibiotic composition was streptomycin, 1 gram; b-acitraoin, 20,000 units; and polymyxin, 80 milligrams. This total dose was administered orally in two or three subdivisions daily for various time periods, usually one to two weeks. Two illustrative case histories are appended.

Case #1.l-./irs. M. K, aged 37, had had diarrhea and abdominal pain and tenderness for the pas n di ation consisted of and various other alleviated the sympstreptoiii sin-polymyii-n-bacitrecin composition, nles after each meal a total of 2a hours i cordless, and diar- This the first time patient had been -cd well to No wil noted.

Gare #L.- 512, had

rrlr a, low abdominal .c ,h and Etoentgenolog one-.. o. colon showed a .re consistent with a d agnosis of chronitive colit Pre u:- i edication cons emyc 11, rest, iron, a d vitamins. 'lihe onondition October, 1946, while he the Navy in the South Pacific, ally disci rged because of his This patient was given the antibiotic 'on for one month. While under treat- '1' annroved, and finally he bee symptom lio toxic effects were e e invention described herein be memonywhere by or for the Gov of the Z ued States for governmental without payment to of any thereon in accordance with the provilone of the act of April 38, 1928 (ch. sec, 45

i claim:

A thera'perdc antibiotic composition for oral administration composed of streptomycin, polymyxin, and bacitracin, said composition becg capable of substantially suppressing coli- .orm bacteria in the intestinal tract without ubstantial adverse effects.

2. A therapeutic antibiotic composition. for oral administration composed of streptomycin, polymyxin, and bacitracin in the following proportions: streptomycin, 250 milligrams; polymyxin, 20 milligrams; bacitracin, 85 milligrams.

3. A therapeutic antibiotic composition for oral administration composed of 250 milligrams of streptomycin, 2c milligrams of polymyxin,

5300 units of bacitracin.

HENRY WELCH.

chronic nd loss cal exolo *ic pici go "I iis m e i REFERENCES CETED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Hegarty et a1. Mar. 6, 1951 ()THER REFERENCES Number 70 her 1945, pages 286 to 291. 167-65P-2. 

1. A THERAPEUTIC ANTIBIOTIC COMPOSITION FOR ORAL ADMINISTRATION COMPOSED OF STREPTOMYCIN, POLYMYXIN, AND BACITRACIN, SAID COMPOSITION BEING CAPABLE OF SUBSTANTIALLY SUPPRESSING COLIFORM BACTERIA IN THE INTESTINAL TRACT WITHOUT SUBSTANTIAL ADVERSE EFFECTS. 